Gut Flora Project Looking For ‘Normal’

The Flemish Gut Flora Project, one of the largest population-wide studies on gut flora variation among healthy volunteers, has presented its first major results. Through the analysis of more than 1,000 human stool samples, a team of researchers led by professor Jeroen Raes (VIB/VUB/KU Leuven) has identified 69 factors that are linked to gut flora composition. These results provide important information for future disease research and clinical studies. The project’s fundamental insights will be published in the upcoming issue of the leading academic journal Science.

2012 marked the launch of the Flemish Gut Flora Project, initiated by prof. Jeroen Raes (VIB/VUB/KU Leuven). Together with his team, prof. Raes aimed at the ambitious task of mapping the gut flora composition of around 5,000 volunteers in Flanders (Belgium). The purpose of this endeavor was to investigate links between the human gut flora and health, diet, and lifestyle.

Gut Flora Composition Linked to Health, Diet, and Lifestyle
Titled “Population-level analysis of gut microbiome variation”, prof. Raes’ study has identified 69 factors associated with gut flora composition and diversity. Most of these covariates are related to transit time, health, diet, medication, gender, and age. Integration of the Flemish Gut Flora Project results with other data sets gathered around the world revealed a set of 14 bacterial genera that make up a universal core microbiota present in all individuals.

Jeroen Raes (VIB/VUB/KU Leuven): “Our research has given us a tremendous amount of new insight into the microbiota composition of normal people like you and me. This makes the Flemish Gut Flora Project unique, since the majority of previous studies focused on specific diseases or featured a significantly smaller geographical scope. However, analyzing the ‘average’ gut flora is essential for developing gut bacteria-based diagnostics and drugs. You need to understand what’s normal before you can understand and treat disease”.

Beer and Buttermilk
Stool transit time showed the strongest association to gut flora composition. Also diet was an important factor, with most associations related to fiber consumption. One of the many surprising findings was the association of a particular bacterial group with a preference for dark chocolate! “The Belgian chocolate effect.”, Raes laughs. “As many readers might expect, we also found an association between gut flora composition and beer consumption.” Other project results incite deeper investigation, such as the relationship between the gut flora and factors linked to oxygen uptake capacity. Medication also had a strong link to the gut flora profile. The Raes Lab researchers not only identified associations with antibiotics and laxatives, but also with hay fever drugs and hormones used for anticonception or alleviation of menopause symptoms. Remarkably, early life events such as birth mode or whether or not volunteers were breast-fed as babies were not reflected in adult microbiota composition.

Jeroen Raes (VIB/VUB/KU Leuven): “These results are essential for disease studies. Parkinson’s disease, for example, is typically associated with a longer intestinal transit time, which in turn impacts microbiota composition. So to study the microbiota in Parkinson’s disease, you need to take that into account. These and many other observations can help scientists in their research into future therapies.”

A key factor in this study was the collaboration with the Dutch LifeLines study, which allowed the researchers to replicate their findings: more than 90% of the identified factors were also detected in the Dutch cohort. International collaborations like these are the key for advancing the field and speed up the path to developing gut flora-based drugs. “Such replication adds a tremendous amount of robustness to the results”, Raes emphasizes. “Of course, we also found some differences between both cohorts. Believe it or not, but one of the important dietary covariates identified in the Dutch cohort was the consumption of buttermilk.”

Tip of the iceberg
Although the Flemish Gut Flora Project has enormously enriched our knowledge on gut flora composition, it only allowed to explain 7% of gut flora variation. An enormous amount of work still needs to be done in order to sketch out the entire gut flora ecosystem. The Raes Lab estimates that around 40,000 human samples will be required just to capture a complete picture of gut flora biodiversity. In other words: we are only seeing the tip of the iceberg. And although the VIB team revealed a wide range of associations, further research is required to unveil what is cause and what is consequence.

This is why this first publication doesn’t mark the end of the Flemish Gut Flora Project. The Raes Lab is already planning follow-up studies, including new large-scale research projects that will explore the evolution of gut flora over time. More volunteers are now being recruited for this long-term study. The more people willing to participate, the faster VIB will be able to unveil new insights into the relationship between the trillions of microbes in the human body and our health. “The thousands of volunteers, pharmacists, and healthcare professionals that participated to the Flemish Gut Flora Project are the heart of this study”, Raes says. “Without their enthusiasm, this couldn’t have been done.”

It appears that the developing gut bacteria in newborns is even more important than previously thought. Antibiotics and other chemical toxins destroy gut bacteria. As the microbiome develops in humans it also determines how our metabolism gets established and our digestive patterns for life are formed according to a NYU research team and published in Cell.

Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity.

We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects.

In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations.